Propionic Acidemia

Most energy in the body is sourced from carbohydrates. Through digestion and metabolism, carbohydrates are broken down into simpler substances like glucose which can be used for energy production. Sometimes when there is insufficient carbohydrates, the body has to depend on proteins and fats for energy. These nutrients have to first be broken down into simpler substances and then converted into glucose by the action of certain enzymes.

Propionic Acidemia Definition

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Propionic acidemia (PA) is a condition where there is an accumulation of propionic acid in the bloodstream. Propionic acid is an intermediate product when amino acids and fatty acids are being converted into glucose. The condition arises from abnormal activity of the propionyl coenzyme A carboxylase (PCC) enzyme which ultimately allows for propionic acid to accumulate in the blood. Propionic acidenmia is an inherent amino acid and fatty acid metabolic crisis that cam cause death in infants within first week of life itself. Although many cases go undocumented, PA affects an estimated, 1 out of every 35000 newborn every year.

Propionic Acidemia Pathophysiology

Protein and fat for energy

When glucose supplies are low, like during starvation or in diabetes mellitus, non-carbohydrate sources like proteins and fats are used for energy production. Proteins and fats from food or internal body stores break down into simpler products – amino acids and fatty acids, respectively. The amino acids and fatty acids are further broken down to produce energy and release nitrogenous wastes that need to be excreted from the body.

Fats and proteins have other functions in the body apart from being a source of energy. Utilization of proteins and fats as fuel-sources leads to ‘wasting’ of organs and formation of ketone bodies, which can affect the normal blood chemistry and functioning of organs. In order to prevent wasting and other consequences of using proteins for energy, proper dietary intake of protein is necessary to compensate for the loss and thus, maintain the nitrogen balance in the body.

Propionyl coenzyme A carboxylase

In order to use amino acids (protein) and fatty acids (fats) for energy, its structure has to be altered for it to become chemically similar to glucose. These compounds have fewer carbon atoms than glucose. In order to achieve this, these compounds have to go through various steps. Propionyl coenzyme A carboxylase catalyzes an important step in this addition of carbon atoms.

When propionyl coenzyme A carboxylase is not functioning optimally, gut bacteria convert partially altered proteins and fats (propionyl CoA) into propionic acid. Over time the propionic acid starts accumulating in the blood leading to acidosis. Biotin, a B-complex vitamin, also plays a role in this process. It is a cofactor for several carboxylase enzymes including propionyl coenzyme A carboxylase. Genetic defects that prevent proper utilization of biotin can therefore impact on propionyl coenzyme A carboxylase. It will also lead to propionic acidemia.

Biotin is required as a cofactor for several carboxylase enzymes including, PCC. Responsiveness towards biotin is a genetic trait. Therefore, a genetic makeup that prohibits normal utilization of biotin may result in presenting PA, either alone or in combination with other carboxylase-deficient symptoms.

Propionic acid in brain

A build-up of acids in the system interferes with the normal functioning of almost every body organ, including the brain. Brain areas responsible for movement and communication (basal ganglia) get severely affected by acidic metabolites. Various theories have been put forward to reason the selective death of basal ganglionic cells. However, none of these hypotheses could sufficiently explain the specific sensitivity of basal ganglionic cells towards propionic acid.

Propionic Acidemia Causes

PCC Genes

Genes, coding for the enzyme propionyl CoA carboxylase, has two subunits – PCCA and PCCB. A defect in any of these forms causes abnormal enzyme functioning. Propionic acidemia is an autosomal recessive disease. Both the parents carrying a copy of diseased gene PCCA or PCCB, are at higher risk of transmitting PA to their children. Individuals having only a single copy of disease-causing gene do not show any symptoms but are known as carriers. Therefore there is a one in four chance that children of carriers will have this gene.

Biotin Genes

Genetic responsiveness towards biotin also constitutes a major predisposal factor for PA. Based on the response towards biotin, PA could exist either alone or in combination of multiple carboxylase deficiencies. Being a genetic disease, each individual presents different degree of severity of symptoms.

Protein-Rich Foods

Intake of protein-rich food tends to complicate propionic acidemia symptoms but is not a cause.

Propionic Acidemia Symptoms

Owing to the defect, a protein-rich diet in propionic acidemia patients becomes life-threatening. Fatty acids contribute to the disease to a lesser extant than proteins. Like most of the other metabolic diseases, propionic acidemia prominently affects brain functions. Based on the time of presentation, propionic acidemia is categorized as early onset or late onset.

Newborns affected by propionic acidemia usually present different symptoms as the disease progresses. Often propionic acidemia presents itself within a few days after birth but few infants face it sometime during their infancy.

First symptoms of propionic acidemia commonly include:

  • Poor appetite
  • Vomiting and dehydration
  • Acidosis
  • Diminished muscle tone
  • Lethargy or extreme sleepiness

If left unattended, these symptoms may aggravate into :

  • Respiratory distress
  • Seizures
  • Brain edema
  • Stroke
  • Coma

Any of these symptoms could immediately become fatal, without presenting any clear signs of morbidity.

In few cases of delayed-onset propionic acidemia, patient present long-term effects including:

  • Delay in development of communication and motor skills
  • Mental retardation with learning disabilities
  • Poor growth and short stature
  • Rigid muscle tone (spasticity)
  • Abnormal involuntary movements (dystonia)
  • Loss of vision

Death associated with propionic acidemia is mainly due to brain damage. Although most babies affected by propionic acidemia do not survive beyond the first year of life, few individuals do not show any symptoms and are diagnosed only upon genetic analysis.

Propionic Acidemia Diagnosis

The low frequency and the non-specific presentation make the diagnosis of propionic acidemia difficult. Some common tests for dignosing propionic acidemiainclude:

  • High levels of propionic acid in the blood
  • Presence of ketones in the urine
  • Concentration of different amino acids in the blood
  • High concentration of glycine in blood
  • Low platelets and WBC count

As it is an inherited disease, the transmission of disease should be carefully examined in both paternal and maternal families. Genetic makeup of siblings could also help in predicting the occurrence of PA.

Pregnant females can be tested by chorionic villi sampling or amniocentesis.

Propionic Acidemia Differential Diagnosis

Propionic acidemia presents a range of non-specific symptoms. To rule out the possibility of propionic acidemia, tests are conducted for other diseases that present with similar symptoms. These diseases include :

  • Other acidurias or carboxylase deficiencies that could increase accumulation of acid in blood.
  • Carbohydrate or other metabolism disorders that could interfere with protein intake and assimilation.
  • Disorders of brain that could precipitate movement and communication abnormalities like encephalopathy, meningitis, stroke and intracranial hemorrhage.
  • Diseases of the blood and heart, like sickle cell anemia, thrombocytopenia, vyanotic heart disease, reduces blood oxygen level. These diseases are present at the time of birth (congenital) and is a major cause of death immediately after birth .

Propionic Acidemia Treatment

There is no cure for propionic acidemia since it is a genetic disease. It can however, be well managed with dietary changes.

Foods to avoid

  • Dietary restrictions offer immediate relief and successfully reverts the symptoms associated with propionic acidemia.
  • Protein-restricted diet (1.5 to 2mg/kg/day) is usually helpful. Regular food intake should be monitored by metabolic dieticians.
  • Carbohydrate-rich food should be given to prevent protein breakdown.
  • Propionic acidemia affected individuals should be fed several times a day to overcome weakness

Supplements

  • L-carnitine supplement (100mg/day) neutralizes the metabolites that accumulate with low-protein diet. It can then be flushe dout in the urine
  • In case of genetic unresponsiveness towards biotin, taking a biotin supplement (10mg/day) and restricting intake of isoleucine, valine, threoine and methionine prove effective.
  • Intravenous glucose administration also helps prevent protein and fat breakdown.
  • Liver transplant is an optional treatment available as the deficient or defective enzyme, propionyl coenzyme A carboxylase, is a liver enzyme.

Other treatment measures

  • Antibiotics, like neomycin and metronidazole, are suggested for gut bacteria that produce propionic acid.
  • Dialysis may be required in extreme cases.
  • Other related signs of dehydration, vomiting and seizures could be treated with suitable medications.

References :

http://ghr.nlm.nih.gov/condition/propionic-acidemia

http://emedicine.medscape.com/article/1161910-overview